Inflammation in the eye often causes the appearance of cells, flare and haze in the anterior and posterior chambers of the eye. A common inflammation is uveitis, which is frequently associated with swelling and inflammation of the uvea, the middle layer of the eye. The uvea consists collectively of the iris, the choroid, and the ciliary body. Uveitis can exist in the front of the eye (anterior uveitis or iritis, hereinafter UV-A), the middle region of the eye (intermediate uveitis, including pars planitis, hereinafter UV-I), the back of the eye (posterior uveitis, hereinafter UV-P), or throughout the eye (panuveitis or diffuse uveitis). The cells present in uveitis are white blood cells that are visible inside the eye. Flare and haze are measures of protein and inflammatory debris within the eye that can appear in active uveitis. Flare is typically associated with anterior uveitis and haze with intermediate and posterior uveitis. Haze/flare is used herein to refer generally to this indicator of inflammation. Manual slit-lamp examination has been the standard method for assessment of the inflammatory reaction in case of uveitis. A variety of classification schemes have been developed and applied to uveitis.
The most common form of uveitis is UV-A, which involves inflammation in the front part of the eye, usually the iris. UV-A can be divided into acute and chronic types based on the duration of the inflammation. A further classification is granulomatous and non-granulomatous. Granulomatous uveitis typically presents with large, greasy precipitates on the corneal endothelium with large clumps of inflammatory cells present in the anterior chamber because of exuberant macrophage activity. Nongranulomatous uveitis typically presents with fine cornea endothelial precipitates and anterior chamber activity (clumps).
A grade or marker for the severity of uveitis can be derived from the number of cells or clumps present in the aqueous humor according to the 2005 Standardization of Uveitis Nomenclature (SUN), which is based upon criteria as defined by the International Uveitis Study Group. This grading system typically uses the information derived from visual inspection using a 1 mm by 3 mm slit beam. For anterior segment cell counts, grade 0 means no cells found and a grade of 4 implies a cell count in excess of 50. Additional classification and grading schemes can include the cell count data as well as factors including the level, origin, location of inflammation, and the amount of haze and/or flare present in different regions of the eye (see, e.g., Madow et al. 2011). These schemes rely heavily on manual examination and interpretation of data. Clinical assessment is subjective and often difficult in eyes with corneal or cataractic opacification from non-uveitic sources.
Optical Coherence Tomography is a non-invasive, in-vivo imaging technique based on the back-scatter or reflectivity of light in a medium (see, e.g., Huang et al. 1991). In ophthalmic examinations, the beam of light produced by the OCT device scans the eye through the pupil and the image formation process records the back-scattering profile of the light at each location. The amount of scatter is indicative of the reflectivity of the tissue encountered, and a grayscale cross-sectional image is formed as the light beam sweeps across the field of view (FOV). OCT imaging has dramatically advanced ophthalmic diagnostic capabilities and led also to better understanding of ocular anatomy. It is now an established basis of routine ophthalmic practice. Several implementations of OCT have been developed including time domain (TD-OCT) and frequency domain (FD-OCT) which covers both spectral domain (SD-OCT) and swept-source (SS-OCT).
The clumps of inflammatory cells present in the anterior chamber of patients with uveitis appear as bright or hyper-reflective spots in OCT images. Thus counting hyper-reflective spots in OCT images can be used to grade uveitis. Methods have been described to determine or assess the risk of uveitis based on intensity levels of the image signal as compared to a database of normal and abnormal values. Agarwal et al. (2009) compared manual and automated counting of the hyper-reflective spots in OCT images of the hyper-reflective spots in anterior chamber. An automated method for identifying, quantifying and classifying cell clumps visible in OCT images is described in U.S. Pat. No. 8,632,180.
Inflammation in the vitreous, as in the anterior chamber, is characterized by increased cells and protein. This increases the level of haze/flare present in the eye. The vitreous is rarely the source of the inflammatory cells; the inflammatory cells arise instead from the choroid, retina, and ciliary body. The cells that form the haze/flare can also be from the breakdown of the blood-ocular barrier. However, in certain infections the focus of the inflammation may be in the vitreous. Both vitreous cells and haze/flare are more difficult to quantify than aqueous cells and haze/flare.
Vitreous haze/flare can be observed in images of the retina and anterior haze/flare could be observed in images of the anterior eye. It is currently the practice to grade vitreous haze/flare by manually comparing the subject's fundus image to “standard” fundus images with the different grades of haze/flare. FIG. 1 shows such a set of standard fundus images with different haze/flare grades (Davis 2012). The grading criteria for the images was: if the nerve fiber layer (NFL) is clearly visible, a grade of 0; if the optic disc or optic nerve head (ONH) and vessels are clear but the visibility of the NFL is hazy, then a grade of 1; for hazy ONH and vessels, a grade of 2; for only ONH visible, the grade of 3; and finally if the ONH is not visible, then a grade of 4. While standard fundus photography was used to collect the images of FIG. 1, various modalities of fundus imaging include SLO (scanning laser ophthalmoscope), cSLO (confocal SLO), LSO (line scanning ophthalmoscope, and BLFI (broad line fundus imager) are capable of producing comparable images for grading of haze/flare.
Posterior uveitis is associated with the highest risk of severe vision loss, and is an inflammation associated with the posterior segment of the eye. The condition can be further characterized based upon whether the retina or the choroid is the predominant site of inflammation. In more severe cases of UV-P, UV-A (cells and flare) is also likely to be present. UV-P inflammation can frequently result in alterations of tissues or layers, such as those in the retina; these often appear as generalized increases in thickness, or local irregularities in the thickness of a layer of interest. Alternately, UV-P can appear as local areas of hyper-reflectivity or hypo-reflectivity within specific layers or tissues.
The evaluation of haze/flare in fundus images is complicated by media opacities that can affect the perception of uveitic haze/flare. The most important degradation is due to the presence of cataracts, a source that can mimic uveitic haze/flare. Separating the effect of such degradations will yield better diagnoses of the etiology of uveitis.
Fundus imaging represents a 2D projection of a 3D system (the eye: anterior, lens, posterior) so provides limited information as to the precise location of the inflammation. OCT provides depth information so can be a useful technique to apply to analyzing the haze/flare in inflamed eyes. A further advantage of the use of OCT for the current application is that infrared light that is used as a probing beam of tissues may have greater penetration through the sites of inflammation, such as haze/flare, than possible with the visual light used in manual examinations.
Proper treatment of inflammation and its efficacy will depend upon accurate and consistent grading of the true inflammation. Subjective or manual grading can add uncertainty in the treatment standards. Thus a methodology that removes some of the uncertainty in the grading should improve the clinical management of uveitis as well as the ability to develop and test effective therapies more efficiently.